Osimertinib (AZD9291) represents a significant advancement in treating specific types of lung cancer. This targeted therapy precisely addresses genetic changes within cancer cells, offering a tailored approach compared to traditional chemotherapy. Its introduction has shifted the landscape of care for patients facing advanced stages of this challenging disease.
Targeting Lung Cancer: The Role of EGFR Mutations
Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 85% of all lung cancer cases, making it the most common form of the disease. A subset of these cancers is characterized by specific genetic alterations in the Epidermal Growth Factor Receptor (EGFR) gene. The EGFR protein normally plays a role in cell growth and division, but when mutated, it can drive uncontrolled cancer cell proliferation.
Common EGFR mutations that make NSCLC responsive to targeted therapies include deletions in exon 19 and a point mutation called L858R in exon 21. These “sensitizing” mutations lead to overactive EGFR signaling, making cancer cells dependent on this pathway for their growth and survival. EGFR tyrosine kinase inhibitors (TKIs) were developed to block this overactive signaling.
Despite initial success with first and second-generation EGFR TKIs, many patients eventually develop resistance, leading to disease progression. A frequent mechanism of this acquired resistance is the emergence of a secondary mutation, T790M, which occurs in approximately 50% to 60% of cases. This T790M mutation alters the EGFR protein in a way that reduces the effectiveness of earlier TKIs, allowing the cancer to continue growing. Overcoming this specific resistance mechanism became a primary focus in lung cancer research.
How AZD9291 Works at a Cellular Level
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI). It specifically targets and irreversibly binds to mutated forms of the EGFR protein, including the T790M resistance mutation. Its mechanism involves forming a covalent bond with a specific residue, C797, in the ATP-binding site of the mutant EGFR, effectively shutting down the overactive signaling pathway that drives cancer growth.
Osimertinib demonstrates a much higher potency, approximately 200-fold greater, against the mutated EGFR (including T790M) compared to the normal, healthy EGFR protein, often referred to as “wild-type” EGFR. This selective targeting helps reduce side effects commonly seen with earlier generation EGFR TKIs, which were less selective and could inhibit wild-type EGFR in healthy cells.
The term “tyrosine kinase inhibitor” refers to a class of drugs that block the activity of enzymes called tyrosine kinases. These enzymes act like switches in cells, turning on various processes, including those that can lead to uncontrolled cell growth in cancer. By inhibiting EGFR tyrosine kinase, Osimertinib interferes with these growth signals, ultimately slowing or stopping the proliferation of cancer cells that rely on this pathway.
AZD9291’s Place in Treatment
Osimertinib, under the brand name Tagrisso, received accelerated approval from the U.S. Food and Drug Administration (FDA) in November 2015. This approval was for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbored the EGFR T790M mutation and had progressed following prior EGFR TKI therapy. The recommended dosage for this indication is 80 mg taken orally once daily.
The effectiveness and safety of Osimertinib were demonstrated in pivotal clinical trials, such as the AURA3 study. This Phase 3 trial randomized patients with EGFR T790M-positive advanced NSCLC who had progressed on first-line EGFR TKI therapy to receive either Osimertinib or platinum-pemetrexed chemotherapy. The AURA3 trial showed that Osimertinib significantly improved progression-free survival (PFS), with a median PFS of 10.1 months compared to 4.4 months for those receiving chemotherapy. Osimertinib also led to a significantly higher overall response rate of 71% versus 31% for chemotherapy.
Beyond its initial use, Osimertinib has also gained approval for first-line treatment in patients with metastatic NSCLC harboring common EGFR mutations, such as exon 19 deletions or exon 21 L858R mutations. This approval was based on data from the FLAURA trial, which showed that Osimertinib monotherapy significantly extended progression-free survival compared to earlier generation EGFR TKIs. More recently, Osimertinib combined with platinum-based chemotherapy has also been approved for first-line treatment in this patient population, demonstrating even longer progression-free survival in the FLAURA2 trial.